Summary The objective of this project is to test a new paradigm for targeting oncoproteins for proteasomal degradation. As we enter the new era of personalized molecular medicine in which next-generation sequencing will rapidly identify somatic mutations in tumor tissues, it is imperative to have a process to develop therapeutic interventions, in a timely manner, against novel cancer-causing proteins beyond those commonly mutated in cancers. In fact, the vast majority of cancer patients do not have those commonly mutated proteins to target therapeutically and drug targeting against rare somatic alterations is too expensive to incentivize drug development against low frequency targets. In order to realize the potential of personalized medicine, rare ?private? mutations must be therapeutically tractable in real-time. Here we will establish a rapid approach for the development of therapeutic agents specific to those private alterations that could be specifically tailored and implemented in real-time to treat each person?s tumor cells. Antagonizing the activity of oncoproteins is currently the major strategy for targeted cancer therapy. This is achieved by using small molecule inhibitors or antagonists to interrupt the signaling pathways of oncoproteins. However, many oncoproteins are undruggable in the sense that inhibiting their signaling pathways has not resulted in clinically useful therapies. This is not completely surprising because an oncoprotein is often involved in multiple signaling pathways, which are so highly interconnected that compensation by parallel pathways can defeat even well conceived therapeutic targeting. In this project, we will exploit a new approach that directly targets oncoproteins for degradation by using bi-functional peptides composed of an aptamer and a degradation signal (degron). As a proof of principle study, we will design and test a degron-aptamer peptide that forces proteasomal degradation ?-catenin, an oncoprotein controlling the transcription of numerous genes related to cancer initiation, progression, and metastasis. Specifically, we will demonstrate targeted degradation of ?- catenin by a degron-aptamer peptide (Aim 1), measure the biological effects of degron-aptamer-mediated degradation of ?-catenin in cancer cells (Aim 2), and optimize the aptamers binding to ?-catenin using structural/computational approaches (Aim 3). In this fashion, we will fundamentally change the approach to targeting oncoproteins by directly forcing their degradation instead of interfering with their signaling pathways. The bi-functional peptide drugs can be designed to not only treat common oncoproteins but can also be developed in real-time for novel, private oncoproteins identified in individual cancer patients.